MX2007000509A - Agent for promoting the recovery from dysfunction after the onset of central neurological disease. - Google Patents

Abstract

It is intended to provide a novel agent for promoting the recovery from dysfunction after the onset of a central neurological disease or an agent for enhancing and/or promoting the effect of rehabilitation for functional recovery. Namely, an agent for promoting the recovery from dysfunction after the onset of a central neurological disease which contains, as the active ingredient, a compound capable of simultaneously and selectively enhancing neurotransmission by serotonin and neurotransmission by norepinephrine; and an agent for enhancing and/or promoting the effect of rehabilitation for functional recovery after the onset of a central neurological disease which contains, as the active ingredient, a compound capable of simultaneously and selectively enhancing neurotransmission by serotonin and neurotransmission by norepinephrine. It is useful to provide the excellent agent for promoting the recovery from dysfunction after the onset of a central neurological disease and the agent for enhancing and/or promoting the effect of rehabilitation for functional recovery as described above. These drugs are also useful as safe drugs because of being free from anticholinergic effect causing side effects, drug dependence or effects on the circulatory organs.

Description

AGENT TO PROMOTE RECOVERY OF DYSFUNCTION AFTER STARTING IN CENTRAL NEU RHEOLOGICAL DISEASE Field of the invention The present invention relates to a pharmaceutical medicament, in particular, an agent for promoting the recovery of dysfunction after the onset of a central neurological disease, and an agent for improving and / or promoting the rehabilitation effect for Functional recovery after the onset of a central neurological disease. Background of the invention Many patients with central neurological disease, such as stroke, brain injury, spinal cord injury, and neurodegenerative disease, are objects of rehabilitation medicine in Japan. These diseases include a variety of disorders: motor dysfunctions such as limb mobility disorders and gait dysfunction, neurological disorders such as hemiplegia, psychiatric disorders such as cognitive deficiency and depressive state, and the like. Drug therapy and rehabilitation for functional recovery are conducted, depending on the progress of a disease condition and severity of the disorder. The index of patients with attack to the patients who are given the rehabilitation medicine is higher. In Japan, the attack is considered approximately 30% of the causes of being bedridden, and the number of patients suffering from its sequel is estimated to be approximately 1.7 million (Guidelines for the Managemnt of Store in Japan , 2004 (The Japan Stroke Society)). Particularly for motor dysfunction due to the attack, it is considered that it is more effective to begin rehabilitation for functional recovery at an early stage after onset. The duration of rehabilitation remains long and yet its effect is not always sufficient. Therefore, a drug is required that can further shorten the duration of rehabilitation for functional recovery and that improves the effect of rehabilitation to the maximum. (S) -2 - [[(7-Fluoro-4-indanyl) oxy] methyl] morpholine hydrochloride (referred to as Compound A subsequently) was found as a compound having an inhibitory effect on the reuptake of serotonin and an antagonism of the 5-HT2A receptor (Patent Document 1). That is, it is reported that Compound A has the effect of improving the neurotransmission of serotonin based on the serotonin reuptake inhibitory activity, as well as the effect of improving norepinephrine neurotransmission based on the antagonism of the 5-HT2A receptor, and its activity is comparable to that of venlafaxine, a serotonin-norepinephrine reuptake inhibitor, described below (Non-patentable Document 1 and Non-patentable Document 2). That is, Compound A is a compound that has the effect of improving the neurotransmissions of both serotonin and norepinephrine. Patent Document 1 discloses that Compound A is useful as a therapeutic drug for secondary symptoms of a cerebrovascular disorder, such as a decrease in spontaneity and depressive mood, and as an agent for improving brain function due to its effect of reinforcement of blood viscosity and antihypoxic effect. However, there is no specific suggestion or description of the effect of promoting recovery from dysfunction, including motor dysfunction due to a central neurological disease, or of the effect of improving and / or promoting the rehabilitation effect for functional recovery. It has been confirmed so far that the improvement of norepinephrine neurotransmission promotes recovery from dysfunction after brain injury (Non-patentable Document 3 and Non-patentable Document 7), and the effect of D-amphetamine, a promoter of the release of monoamine, has been well studied (Non-patentable Document 4, Non-patentable Document 5 and Document Not patentable 6). Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), has also been reported to be effective for the recovery of motor function (Non-Patentable Document 8).

Based on these results, compounds that have the effect of improving the neurotransmission of norepinephrine neurons or serotonin neurons are considered to be effective in promoting the recovery of dysfunction after the onset of a central neurological disease. However, D-amphetamine causes adverse drug reactions such as drug dependence, excitation effect, and effects on the circulatory system, and the effect of fluoxetine to promote functional recovery is insufficient with respect to that of D-amphetamine. (Non-patentable document 9). Therefore, drugs that are safer and have excellent efficacy are desired. Patent Document 1: International Patent Publication WO94 / 1 8182 Pamphlet Non-patentable Document 1: Eur. J. Pharmacol. 395 (1), 31 -36, 2000 Non-patentable Document 2: J. Pharmacol. Exp. Ther. 302 (3), 983-991; 2002 Non-patentable Document 3: Science 217, 855-857, 1982 Non-patentable Document 4: Stroke 29, 2381 -2395, 1 998 Non-Patentable Document 5: Ann. Neurol. 23, 94-97, 1988 Non-patentable document 6: Stroke 26, 2254-2259, 1 995 Non-patentable document 7: J. Phys. Med. Rehabil. 72, 286-293, 1993 Documents Not patentable 8: Stroke 27, 1 21 1 -1 214, 1 996 Document Not patentable 9: Am. J Phys. Med, Rehabil 73, 76-83, 1994 Description of the Invention Problems to be Resolved by the Invention One object of the present invention is to provide a pharmaceutical medicament useful as an agent to promote the recovery of dysfunction after the onset of a central neurological disease, and agent to improve and / or promote the effect of rehabilitation for functional recovery after the onset of a central neurological disease. Particularly, an object of the present invention is to provide a pharmaceutical drug superior to conventionally known drugs, fluoxetine, desipramine, and D-amphetamine, in terms of promotion and / or effects of prior improvement or reduction in adverse drug reactions. Means for Problem Solving The present inventors further study drugs that promote recovery from dysfunction due to a central neurological disease, and as the result confirmed that the compounds simultaneously and selectively improve the neurotransmission of serotonin and neurotransmission of norepinephrine, especially Compound A, they have an excellent effect to promote recovery of motor functions, and complete the present invention. That is, the present invention relates to an agent for promoting recovery from dysfunction after the onset of a central neurological disease such as stroke, brain injury, neurodegenerative disease, and spinal cord injury, comprising a compound that improves simultaneously and selectively the neurotransmission of serotonin and norepinephrine neurotransmission as an active ingredient; and an agent for improving and / or promoting the effect of rehabilitation for functional recovery after the onset of a central neurological disease, comprising a compound that simultaneously and selectively improves the neurotransmission of serotonin and neurotransmission of norepinephrine as an active ingredient. Effects of the Invention The present invention is useful in providing an excellent agent for promoting recovery from dysfunction due to a central neurological disease and an agent for improving and / or promoting rehabilitation for functional recovery. The pharmaceutical medicament of the present invention is useful as a safe drug free from adverse drug reactions due to an anticholinergic effect, such as dry mouth, constipation, dysuria, and blurred vision, or drug dependence. Especially, Compound A is superior to conventionally known drugs, fluoxetine, desipramine, and D-amphetamine, in terms of promotion and / or effect of prior improvement or reduction in adverse drug reactions. further, Compound A has a protective effect on mitochondrial dysfunction and affinity to sigma receptors, as well as an inhibitory effect on cell death due to attack, and the effect of improving neurite outgrowth, and is useful as a therapeutic agent of the present invention. BEST MODE FOR CARRYING OUT THE INVENTION Preferred aspects of the present invention will be described in the following items (1) to (8). (1) An agent for promoting recovery from dysfunction after the onset of a central neurological disease, comprising a compound that simultaneously and selectively improves the neurotransmission of serotonin and neurotransmission of norepinephrine as an active ingredient. (2) An agent for improving and / or promoting the effect of rehabilitation for functional recovery after the onset of a central neurological disease, comprising a compound that simultaneously and selectively improves the neurotransmission of serotonin and norepinephrine neurotransmission as an active ingredient. (3) The agent described in item (1) or (2), wherein the central neurological disease is an attack, brain injury, spinal cord injury, or neurodegenerative disease. (4) The agent described in item (3), wherein the dysfunction is a motor dysfunction, sensory function disorder or language function disorder. (5) An agent to promote the recovery of dysfunction after the onset of a central neurological disease comprising duloxetine, venlafaxine, milancipran, or (S) -2 - [[(7-fluoro-4-indanyl) oxy] methyl] morpholine or a pharmaceutically acceptable salt thereof as an active ingredient. (6) An agent for improving and / or promoting the rehabilitation effect for functional recovery after the onset of central neurological disease, comprising duloxetine, venlafaxine, milnacipran, or (S) -2 - [[(7-fluoro- 4-indanyl) oxy] methyl] morpholine or a pharmaceutically acceptable salt thereof as an active ingredient. (7) The agent described in item (5) or (6), wherein the central neurological disease is attack, brain injury, spinal cord injury, or neurodegenerative disease. (8) The agent described in item (7), wherein the dysfunction is motor dysfunction, sensory function disorder, or language function disorder. (9) An agent for promoting recovery of dysfunction after the onset of a central neurological disease, comprising a compound having an inhibitory effect of serotonin reuptake and 5-HT2A receptor antagonism, as an active ingredient. (10) An agent for improving and / or promoting the effect of rehabilitation for functional recovery after the onset of a central neurological disease, comprising a compound having a serotonin reuptake inhibitory effect and antagonism of the 5-HT2A receptor , as an active ingredient. (11) The agent described in item (9) or (10), wherein the central neurological disease is attack, brain injury, spinal cord injury, or neurodegenerative disease. (12) The agent described in item (11), where the dysfunction is motor dysfunction, sensory function disorder, or language function disorder. The other preferable aspects of the present invention will be described in the following items (1 3) to (18). (13) An agent for promoting recovery from dysfunction after the onset of a central neurological disease, comprising (S) -2 - [[(7-fluoro-4-indanyl) oxy] methyl] morpholine or a pharmaceutically salt acceptable from it, as an active ingredient. (14) An agent to improve and / or promote the effect of rehabilitation for functional recovery after the onset of a central neurological disease, comprising (S) -2 - [[(7-fluoro-4-indanyl) oxy] methyl ] morpholine or a pharmaceutically acceptable salt thereof as an active ingredient. (15) The agent described in item (13) or (14), wherein the central neurological disease is attack, brain injury, spinal cord injury, or neurodegenerative disease. (1 6) The agent described in point (1 5), where the dysfunction is motor dysfunction, sensory function disorder, or language function disorder. (17) An agent for promoting the recovery of motor dysfunction after the onset of the attack, comprising (S) -2 - [[(7-fluoro-4-indanyl) oxy] methyl] morpholine or a pharmaceutically acceptable salt of the same, as an active ingredient without causing an increased heart rate or excitation effect. (18) An agent that improves and / or promotes the rehabilitation effect for the recovery of motor dysfunction after the onset of the attack, which comprises (S) -2 - [[(7-fluoro-4-indanyl) oxy] methyl ] morpholine or a pharmaceutically acceptable salt thereof, as an active ingredient without causing an increased heart rate or excitation effect. The present invention will be described in more detail. The "compound that simultaneously and selectively improves the neurotransmission of serotonin and neurotransmission of norepinephrine", means a compound that has an effect to simultaneously improve both the neurotransmission of serotonin and the neurotransmission of norepinephrine through the inhibition of absorption or promotion of release of serotonin and norepinephrine, ie, no compound that selectively improves serotonin neurotransmission (e.g., fluoxetine) or any compound that selectively improves norepinephrine neurotransmission (e.g., desipramine) is included in the active ingredient of the present invention. The "compound that simultaneously and selectively improves the neurotransmission of serotonin and neurotransmission of norepinephrine" does not include compounds that improve neurotransmission via dopamine, a class of monoamine. In other words, conventionally known D-amphetamine is not included in the active ingredient of the present invention, since it promotes the release of monoamines, but is not a compound that simultaneously and selectively improves the neurotransmission of serotonin and neurotransmission of norepinephrine. The active ingredient of the present invention includes, specifically SNRI and Compound A, and Compound A is particularly preferred. "SNRI" is a drug that has selective serotonin and norepinephrine uptake inhibitory effects, specifically including milnacipran (Asahí Kasei Corporation), venlafaxine (Wyeth), duloxetine (Lilly), F-98214-TA (FAES Farma), and the like. It should be noted that, although milnacipran, venlafaxine, and duloxetine are known as "antidepressants", they are not recognized as the agent of the present invention to promote recovery from dysfunction after the onset of a central neurological disease or agent to improve and / or promote the effect of rehabilitation for functional recovery after the onset of a central neurological disease. "Dysfunction after the onset of a central neurological disease" means motor dysfunction, sensory function disorder, language function disorder, and the like caused by the disorder of nerve functions controlled by sites damaged by the attack, injury of brain, neurodegenerative diseases, spinal cord injury, and the like. Psychiatric disturbance such as depressive symptom or cognitive deficiency such as dementia is not included. The dysfunction to which the present invention is preferably applied is motor dysfunction. "Attack" is classified as hemorrhagic and non-hemorrhagic. Examples of hemorrhagic attack include cerebral hemorrhage, subarachnoid hemorrhage, and intracranial hemorrhage secondary to cerebral arterial malformation, while examples of non-hemorrhagic stroke include cerebral infarction. "Brain injury" refers to a condition in which the brain is traumatically damaged by the injury caused in a traffic accident or the like, including brain contusion, epidural hematoma, subdural hematoma, intracerebral hematoma, diffuse axonal injury, and the like . "Spinal cord injury" refers to a condition in which the spinal cord receives compression / wear due to a fracture or vertebral dislocation due to dysfunction. The "neurodegenerative disease" refers to a syndrome with chronic and progressive death of neuronal cells that belong to a particular functional system. Examples thereof include Parkinson's disease, spinocerebellar degeneration, multiple systematic atrophy, lateral sclerosis, amyotrophic, and the like. "Motor dysfunction" refers to a condition with which performing voluntary movements is difficult, impossible, or non-uniform, which means paralysis and motor ataxia. Specifically, it is a disorder of movement ability, Babniski's sign, spastic paralysis, spasticity (chronic phase), increased deep tendon reflex (chronic phase), muscle rigidity, bradypraxia, involuntary movement (tremors, choreic movement, athetosis, dystonia, etc.). .), ataxia (extremities and torso), language function disorder, or dysphoria / allyment disorder. The present invention is preferably applied to gait dysfunction and impairment of upper extremity function. "Sensory function disorder" refers to a condition in which the brain disorder impairs the correct recognition of superficial sensation such as tactile sensation, barrosity, and thermosetting.; deep sensation such as sensation of position and palesthesia; combined feeling such as two-point discrimination and graffiti, or the like. It is classified according to severity in anesthesia (sensory extinction), hyperesthesia (sensory poverty), hyperesthesia, and disaesthesia (paresthesia). It also includes sensory function disorders characterized by the site of incidence, such as middle-body disesthesia, superficial sensation disorder, and total sensation disorder. "Language function disorder" refers to aphasia characterized by decreased ability in terms of language, such as hearing, reading, speaking and writing words because of damage in the region that controls a language function; and dysarthria characterized by symptoms such as dysphonia and phonation disorder due to the paralysis of the phonic and speech organs such as the lips, tongue and vocal cords or mismatch of movement (ataxia). The present invention is preferably applied to dysarthria due to motor dysfunction. The "promotion of dysfunction recovery" means the recovery of the previous dysfunction before and at a higher level for the purposes of shortening a period of hospitalization, and of promoting the early independence and improvement of the quality of life (QOL). ), and similar after the start. The application of the present invention is preferably related to motor dysfunction due to attack, brain injury, neurodegenerative disease, or spinal cord injury, preferably to gait dysfunction and dysfunction of the upper extremity after the attack. "Rehabilitation for functional recovery" refers to rehabilitation for the recovery of motor functions, such as muscle strengthening exercise, range of motion exercise of the fingers, knees and the like, movement exercise such as walking; rehabilitation for the recovery of language functions; rehabilitation for the recovery of cognitive functions, and the like that are conducted in the acute phase, recovery phase, and maintenance phase according to the time after the onset of a central neurological disease and the condition of a patient. The present invention is preferably applied to rehabilitation for the recovery of motor functions. The "improvement of the effect of rehabilitation for functional recovery" means the recovery of a function to a higher level, and the additional mitigation of a disorder compared to the case of driving rehabilitation alone. The "promotion of the effect of rehabilitation for functional recovery" means the promotion of functional recovery in a shorter period compared to that driven by rehabilitation alone. (S) -2 - [[(7-fluoro-4-indanyl) oxy] methylene] morpholine and its pharmaceutically acceptable salts can be easily obtained by the manufacturing method described in Patent Document 1 or methods of manufacturing similar to it. Milnacipran can be obtained easily by the method described in US Pat. No. 4,778,836, venlafaxine by the method described in British Patent No. GB2227743, duloxetine by the method described in US Pat. No. 5,382,886, and F-98214-TA. by the method described in Journal of Medicinal Chemistry (2003), 46 (25), 551 2-5532 or methods similar to them. Compound A can form salts with acids together with hydrochloride. Such salts are included in the present invention as long as they are pharmaceutically acceptable salts. Specifically, examples of acids include inorganic acids such as hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, aspartic acid, and glutamic acid. Compound A includes various hydrates, solvates, and polymorphism of its free form and pharmaceutically acceptable salts. The preparation of the present invention can be prepared using carriers for pharmaceuticals, excipients and the like commonly used in the art, by methods normally used. Administration can be oral administration using tablets, pills, capsules, granules, powder, liquid, and the like, or parental administration using injections such as intra-articular, intravenous, intramuscular, intramuscular injections, suppositories, eye drops, ocular ointment, percutaneous fluid , ointment, percutaneous patch, transmucosal fluid, transmucosal patch, inhalant, and the like. The form of the solid composition for oral administration according to the present invention includes tablet, powder, granule, and the like. For such a solid composition, one or more active ingredients are mixed with at least one inert diluent, for example, lactose, mannitol, glucose, hydroxypropicellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, and / or magnesium aluminate metasilicate. The composition may contain, according to conventional manners, additives other than inert diluents exemplified by lubricants such as magnesium stearate, disintegrants such as calcium gluconate cellulose, stabilizers, and solubilization aids. The tablets and pills can be coated with sugar, such as sucrose, gelatin, hydroxypropicellulose, hydroxypropylmethylcellulose phthalate and the like, or a film of a gastric or enteric substance. The form of the liquid composition for oral administration includes a pharmaceutically acceptable emulsion, solution, suspension, syrup, elixir, or the like, and the liquid composition contains an inert diluent generally used, for example, purified water or ethanol. The liquid composition may contain auxiliaries such as solubilizing agents, humectants, and suspending agents, sweeteners, flavors, aromatics, or preservatives in addition to the inert diluent. The injection for parenteral administration contains a sterile aqueous or non-aqueous solvent, suspension medium, or emulsion medium, the aqueous solvent or suspension medium includes distilled water for injection and physiological saline. The non-aqueous solvent or suspension medium is exemplified by propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, Polysolvate 80 (name in Japanese Pharmacopeia), and the like.

These compositions may also contain toning agents, preservatives, humectants, emulsifiers, dispersing agents, stabilizers, or solubilization aids. These compositions are sterilized, for example, by filtration through a bacteria retention filter, by the addition of a bactericide, or by irradiation. Alternatively, a sterile solid composition can be prepared and, before use, dissolved or suspended in sterile water or sterile solvent for injection. Transmucosal preparations such as a transnasal preparation can be solid, liquid or semi-liquid and can be manufactured according to conventionally known methods. For example, publicly known pH adjusters, preservatives, thickeners, and excipients may be added as appropriate and the composition formed in the solid, liquid or semi-liquid state. The transnasal preparation is administered through an ordinary aerosol apparatus, nasal spray, tube, an insert for the nasal cavity, or the like. The drug used in the present invention is administered to patients who have dysfunction, after the onset of a central neurological disease, preferably to patients immediately after 6 months after onset, during the rehabilitation period for functional recovery (1 month to 1 year maximum, preferably 3 to 6 months). A suitable daily dose for oral administration is generally about 0.01 to 1000 mg, preferably 0.1 to 300 mg / kg, more preferably 0.1 to 100 mg, and the daily dose is administered once or divided into 2 to 4 daily portions during the rehabilitation period for functional recovery. For intravenous administration, an appropriate daily dose is from about 0.001 to 1000 mg / kg of body weight and the daily dose is administered once or divided into several daily portions. A dose can be determined individually according to symptoms, age, sex, and the like. EXAMPLES The present invention will be illustrated in more detail with reference to the examples. EXAMPLE 1 Evaluation Test for the Marching Function in a Rat Model with Brain Infarction A rat model with cerebral infarction was prepared according to the method described in J. Cereb. Blood Flow Metab. 8, 474-485, 1 988.

Rats with spontaneous male hypertension (Hocino Laboratory Animals) weighing 278-350 g were used at the time of the operation and a cerebral infarction was prepared by obstructing the left common carotid artery and the left middle cerebral artery. The gait function was evaluated using a beam-walking test and a one-foot test according to the method described in J. Neurotrauma 13, 293-307, 1 996. In the test of walking on a beam, the The ability to walk when walking on a beam of 1 8 mm wide and 1 22 cm long was recorded in 7 degrees (7 corresponds to normal and 1 corresponds inability to walk). In the lack of foot test, when walking in a 53 cm x 36 cm grid with a trellis size of 6.5 mm2 for 2 minutes, a percentage of the number of foot glide with respect to the total number of steps of the foot was measured. front leg on the side of the disorder. The tests were conducted immediately before the cerebral infarction preparation, 2, 3, and 5 days after the preparation of the cerebral infarction, and after the same two times a week. Compound A and fluoxetine were administered after the measurement of the prodrug values at 2 days after the preparation of the cerebral infarction and the treatment continued until the end of the evaluation. Compound A was administered 45 minutes before the walking test and fluoxetine was administered 60 minutes before the tests. The distilled water in the same volume was administered to the control group. D-amphetamine was administered intraperitoneally 60 minutes before the tests of the walking function from 3 days to 2 weeks after the preparation of the cerebral infarction. Physiological saline was administered in the same volume to the control group. From the observed values, the corresponding prodrug values were subtracted, and statistical analysis was carried out through the repeated analysis of two variation pathways, when a significant difference was observed, a multiple comparison was conducted. The results are shown in figs. 1 to 3. As shown in fig. 1, Compound A exhibited a significant improvement effect compared to the control group in the walking test on a beam (a) and the foot failure test (b) [walking test on a beam: analysis of two ways of variation; p-value = 0.0096 for the treatment effect, p-value < 0.00 1 for affect of time, value-p = 0.021 for interaction. Multiple comparison; *: p < 0.05, **: p < 0.01 (10 mg / kg against vehicle), #: p < 0.05, ##: p < 0.01 (5 mg / kg against vehicle). Proof of foot failure; analysis of two variation pathways; p-value = 0.0019 for the treatment effect, p-value < 0.001 for the effect of time, p-value = 0.022 for the interaction. Multiple comparison; *: p < 0.05 (10 mg / kg against vehicle), #: p < 0.05, ##: p < 0.01 (5 mg / kg against vehicle)). As shown in fig. 2, D-amphetamine exhibited an affect of significant improvement compared to the control group in the test of walking on a beam (a) [analysis of two-way variation; p-value = 0.0055 for the treatment effect, p-value < 0.001 for the effect of time, value-p < 0.001 for interaction. Multiple comparison; ***; p < 0.0001 (1.5 mg / kg against vehicle), #: p < 0.05, ##: p < 0.01 (0.75 mg / kg against vehicle)). However, in the foot test, although a trend towards improvement was observed compared to the control group, the effect was not significant. As shown in fig. 3, fluoxetine did not exhibit any evident improvement effect compared to the control group the test walk on a beam (a) and the lack of foot test (b). Accordingly, the above tests showed that Compound A has a promotion effect on recovery from gait function disorder caused by cerebral infarction, superior to D-amphetamine and fluoxetine.

Example 2 Evaluation Test for the Function of the Front Leg in the Rat Model with Cerebral Nerve (Stair Test) Rats with spontaneous male hypertension weighing 251 to 339 g (Hocino Laboratory Animáis) were used. The function of the front leg was evaluated using a staircase test (a test using a box in which a base was placed and the stairs were fixed in parallel on the left and right sides of the base inside an acrylic box that has one size to fit a rat) according to the method described in J. Neurosci. Methods 36, 219-228, 1991. A rat for which feeding had been limited before the experiment was placed on a ladder and trained to acquire the ability to eat the food pills fixed in a dent at each step of the ladder before counting. The numbers of displaced pills and numbers of pills eaten were counted for the right front and left legs. After acquiring the ability to eat, cerebral infarction was prepared as in example 1. Compound A was administered orally at a dose of 5 mg / kg five times per week starting next week, which follows the preparation of cerebral infarction, until week 6. D-amphetamine was administered intraperitoneally at a dose of 1.5 mg / kg twice a week from next week, which follows the preparation of the cerebral infarction, until week 6. The distilled water or physiological saline in the same amount was administered to the control group. The test was conducted 60 minutes after the administration of the drug. The efficacy of the drug was analyzed by Dunnett's multiple comparison. The results are shown in fig. 4. As shown in fig. 4, the dysfunction of the front leg is compared using the number of displaced pills as indexes (a) and the number of pills eaten (b) in the staircase trial, indicating that a significant improvement effect was observed in the group of Compound A compared to the control group (*: p <0.05, ** : p <0.01 against vehicle). Although a trend towards improvement was observed in the D-amphetamine group compared to the control group, the effect was not significant. Accordingly, the above test shows that Compound A has a promotion effect in recovering front leg dysfunction caused by the attack, superior to that of D-amphetamine. Example 3 Evaluation of the Effect on the Locomotor Activity The effects of D-amphetamine and Compound A on locomotor activity were evaluated with the number of total steps in the foot failure test in Example 1. The statistical analysis was conducted by the repeated measures analysis of two variation pathways.

When a significant difference was observed, Dunnett's multiple comparison was conducted. The results are shown in fig. 5. As shown in fig. 5, an excitation effect was developed and a marked increase in the number of steps in the previous test was observed during the administration period in the D-amphetamine group (a) [two-way variation analysis; p-value 0.001 for the treatment effect, p-value < 0.00 1 for the effect of time, value-p < 0.001 for interaction. Multiple comparison; ***; p < 0.001 (1.5 mg / kg against vehicle), ###: p < 0.001 (0.75 mg / kg against vehicle)]. On the other hand, no effect was observed on the number of steps in the group of Compound A (b). Accordingly, it was revealed that D-amphetamine simultaneously exhibits an unfavorable excitation effect, in the dose exhibiting efficacy of the drug in functional recovery, while Compound A does not have such an unfavorable effect. Example 4 Evaluation of the Effect on the Circulatory System Rats with spontaneous male hypertension (Hocino Laboratíry Animáis) weighing 240 to 275 g after a cannula was inserted into the common carotid artery were used., heart rhythms were monitored. Compound A or D-amphetamine was administered orally or intraperitoneally, respectively, and cardiac rhythms were recorded up to 4 hours after administration. For the control group, physiological saline was administered intraperitoneally and the measurement was similarly conducted. The statistical analysis was conducted by the repeated measurement analysis of a variation path. When a significant difference was observed, a multiple comparison was applied by the two-way Dunnet method. The results are shown in fig. 6 As shown in Fig. 6, a significant increase in heart rate was observed from 30 minutes to 1 hour after administration in the D-amphetamine group (a) (one-way analysis: p-value <0.001, multiple comparison; ** *: p <0.001, *: p <0.05 against basic value). On the other hand, no effect on cardiac rhythm was observed in the group of Compound A (b) or control group (c). Accordingly, it was revealed that D-amphetamine also exhibits an unfavorable affect, an accentuation of the heart rate (circulatory effect), at the dose exhibiting the efficacy of the drug in functional recovery, whereas Compound A does not have such an unfavorable effect. In the conclusion, with respect to Compound A and fluoxetine, as shown in Figs. 1 to 3, Compound A exhibited an improvement affec- tion better than fluoxatine in the walking test on a beam and the foot test. Accordingly, Compound A is more useful than fluoxetine as an agent for promoting recovery from dysfunction after the onset of a central neurological disease and as an agent for improving and / or promoting the rehabilitation effect for functional recovery after the beginning of a central neurological disease. With respect to Compound A and D-amphetamine, as shown in Figs. 1, 2, and 4, it is found that Compound A has a drug efficacy equal to or better than D-amphetamine in the test of walking on a beam, proof of foot failure, and the staircase test. In addition, it is found from figs. 5 and 6 that D-amphetamine also exhibits unfavorable side effects such as an excitation effect and an accentuation of the heart rate at a dose exhibiting the same efficacy. Accordingly, Compound A is an agent for promoting recovery from dysfunction after the onset of a central neurological disease and an agent for improving and / or promoting the affection of rehabilitation for functional recovery after the onset of a central neurological disease, which has a wider safety range than D-amphetamine and has no adverse drug reaction at a dose that exhibits the efficacy of the drug. Brief Description of the Drawings Fig. 1 shows the effect of improvement of Compound A on the function of walking in the test of walking on a beam (a) and the lack of foot test (b). (example 1) (in the figure, the "record" represents records of the test of walking on a beam, the "day after MCAo" represents the days after the preparation of the cerebral infarction, the "% of foot faults" represents a percentage of the number of foot slides with respect to the total number of steps in the foot test, and the "vehicle" represents the control group that receives the solvent). Fig. 2 shows the effect of D-amphetamine on the function of gait in the test of walking on a beam (a) and the lack of foot test (b). (example 1) (The symbols in the figure are the same as before). Fig. 3 shows the effect of fluoxatine on the function of gait in the test of walking on a beam (a) and the lack of foot test (b). (example 1) (The symbols in the figure are the same as before). Fig. 4 shows the effect of Compound A and D-amphetamine on the function of the front leg, with the number of displaced food pills (a) and the number of pills eaten (b) as indexes. (example 2) (In the figure, the "Total Number of Pills (D)" represents the number of displaced pills, the "Total Number of Pills (E)" represents the number of pills eaten, the "Left Foot" represents a front leg on the healthy side, the "Right leg" represents the front leg on the side with disorder, "V" represents the control group that receives the solvent, the "A p" represents the group of D-amphetamine, and "Cpd. A" represents the group of Compound A). Fig. 5 shows the changes in the number of steps in the D-amphetamine group (a) and the group of Compound A (b). (example 3) (In the figure, "Step No." represents the number of steps in the foot test, and the other symbols are the same as those in Figure 1). Fig. 6 shows the changes in heart rate in the group of D-amphetamine (a), the group of Compound A (b), and the control group (c). (example 4) (In the figure, "% Change in HR" represents the rate of changes in heart rate, and "time after dosing (hr) "represents the time after administration." Industrial Applicability As described above, the present invention can be applied as a drug, particularly as an agent to promote the recovery of dysfunction after the onset of a central neurological disease, and an agent to improve and / or promote the rehabilitation effect for functional recovery after the onset of central neurological disease.

Claims (10)

1. CLAIMS 1 . An agent for promoting recovery from dysfunction after the onset of a central neurological disease, comprising a compound that simultaneously and selectively improves the neurotransmission of serotonin and neurotransmission of norepinephrine as an active ingredient. 2. An agent for improving and / or promoting the rehabilitation effect for functional recovery after the onset of a central neurological disease, comprising a compound that simultaneously and selectively improves the neurotransmission of serotonin and neurotransmission of norepinephrine as an active ingredient. The agent according to claim 1 or 2, wherein the central neurological disease is an attack, brain injury, spinal cord injury, or neurodegenerative disease. 4. The agent according to claim 3, wherein the dysfunction is motor dysfunction, sensory function disorder, or language function disorder. 5. An agent to promote recovery from dysfunction after the onset of a central neurological disease, comprising duloxetine, venlafaxine, milnacipran, or (S) -2 - [[(7-fluoro-4-indanyl) oxy] [methyl] morpholine or a pharmaceutically acceptable salt thereof as an active support ing. 6. An agent for improving and / or promoting the effect of rehabilitation for functional recovery after the onset of a central neurological disease, comprising duloxetine, venlafaxine, milnacipran, or (S) -2 - [[(7-fluoro-4 -indanyl) oxy] methyl] morpholine or a pharmaceutically acceptable salt thereof as an active ingredient. 7. The agent according to claim 5 or 6, wherein the central neurological disease is an attack, brain injury, spinal cord injury, or neurodegenerative disease. 8. The agent according to claim 7, wherein the dysfunction is motor dysfunction, sensory function disorder, or language function disorder. 9. An agent for promoting recovery from dysfunction after the onset of a central neurological disease, comprising a compound having an inhibitory effect of serotonin reuptake and antagonism of the 5-HT2A receptor as an active ingredient. 10. An agent for improving and / or promoting the effect of rehabilitation for functional recovery after the onset of a central neurological disease, comprising a compound having an inhibitory effect of serotonin reuptake and antagonism of the 5-HT2A receptor as an active ingredient. eleven . The agent according to claim 9 or 10, wherein the central neurological disease is an attack, brain injury, spinal cord injury, or neurodegenerative disease. The agent according to claim 1, wherein the dysfunction is motor dysfunction, sensory function disorder, or language function disorder. 13. An agent for promoting recovery from dysfunction after the onset of a central neurological disease, comprising (S) -2 - [[(7-fluoro-4-indanyl) oxy] methyl] morpholine or a pharmaceutically acceptable salt of the same as an active ingredient. 14. An agent to improve and / or promote the effect of rehabilitation for functional recovery after the onset of a central neurological disease, comprising (S) -2 - [[(7-fluoro-4-indanyl) oxy] methyl ] morpholine or a pharmaceutically acceptable salt thereof as an active ingredient. The agent according to claim 1 3 or 14, wherein the central neurological disease is an attack, brain injury, spinal cord injury, or neurodegenerative disease. 16. The agent according to claim 15, wherein the dysfunction is motor dysfunction, sensory function disorder, or language function disorder. 17. An agent for promoting the recovery of motor dysfunction after the onset of an attack, comprising (S) -2 - [[(7-fluoro-4-andanyl) oxy] methyl] morpholine or a pharmaceutically acceptable salt of the same as an active ingredient without causing an accentuation of the heart rate or excitation effect. 18. An agent that improves and / or promotes the rehabilitation effect for the recovery of motor dysfunction after the start of an attack, which comprises (S) -2 - [[(7-fluoro-4-indanyl) oxy] methyl] morpholine or a pharmaceutically acceptable salt thereof as an active ingredient without causing an increased heart rate or excitation effect.